Transcript Powerpoint Presentation

Ionizing and Non-Ionizing RadiationInduced Adaptive Response: Findings
From Earth to Space
SMJ Mortazavi
Prof. of Medical Physics
Shiraz University of Medical Sciences
[email protected]
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Paracelsus (1493-1541)
• "All substances are
poisons; there is none
which is not a poison.
• The right dose
differentiates a
poison…."
Mortazavi SMJ, Ph.D
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Hormesis
• All chemical substances will exhibit a toxic
effect given a large enough dose.
• If the dose is low enough even a highly toxic
substance will cease to cause a harmful
effect.
• The toxic potency of a chemical is thus
ultimately defined by the dose (the amount)
of the chemical that will produce a specific
response in a specific biological system.
• Source:
http://learn.caim.yale.edu/chemsafe/references/dose.html
Mortazavi SMJ, Ph.D
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LNT & Radiation Hormesis
• The radiation hormesis model, unlike the LNT
model, assumes that adaptive/protective
mechanisms can be stimulated by low-dose
radiation and that they can prevent both
spontaneous and toxicant-related cancers as
well as other adverse health effects (Calabrese
et al. 2007).
Mortazavi SMJ, Ph.D
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Natural radiation deficiency
symptoms
 It has been long
known that protozoa
and bacteria exposed
to artificially lowered
levels of natural
radiation
demonstrate
deficiency symptoms
expressed as
dramatically
decreased
proliferation.
Mortazavi SMJ, Ph.D
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Ph.D
Radon & Lung Cancer in Ramsar, Iran
 Radon levels in some dwellings are up to 3700 Bq/m3
(over 100 pCi/L).

 The people and their ancestors exposed to abnormally
high radiation levels over many generations.
 If a radiation dose of a few hundred mSv per year is
detrimental to health causing genetic abnormalities or
an increased risk of cancer, it should be evident in these
people.
Mortazavi SMJ, M. Ghiassi-Nejad and M. Rezaiean. Cancer risk due to exposure to
high levels of natural radon in the inhabitants of Ramsar, Iran in: High Levels of
Natural Radiation and Radon Areas: Radiation Dose and Health Effects, T. Sugahara,
M. Morishima, M. Sohrabi, Y Sasaki, I. Hayata, and S. Akiba Eds, pp. 436-437,
Elsevier, Amsterdam, 2005.
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Ph.D
Study Design
• Ramsar was divided into eight health districts
and a health center provided primary health
services in each health district.
• Indoor radon concentration levels were
previously measured in each dwelling by the
Iranian Nuclear Regulatory Authority experts.
Mortazavi SMJ, M. Ghiassi-Nejad and M. Rezaiean. Cancer risk due to exposure to
high levels of natural radon in the inhabitants of Ramsar, Iran in: High Levels of
Natural Radiation and Radon Areas: Radiation Dose and Health Effects, T. Sugahara,
M. Morishima, M. Sohrabi, Y Sasaki, I. Hayata, and S. Akiba Eds, pp. 436-437,
Elsevier, Amsterdam, 2005.
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Cancer Mortality
Mortazavi SMJ,
Ph.D
• The overall cancer mortality, lung cancer
mortality and neonatal death rate of different
districts in the years from 2000 to 2001 were
collected.
• The radon prone houses were located in a district
named Ramak.
Mortazavi SMJ, M. Ghiassi-Nejad and M. Rezaiean. Cancer risk due to exposure
to high levels of natural radon in the inhabitants of Ramsar, Iran in: High Levels
of Natural Radiation and Radon Areas: Radiation Dose and Health Effects, T.
Sugahara, M. Morishima, M. Sohrabi, Y Sasaki, I. Hayata, and S. Akiba Eds, pp.
436-437, Elsevier, Amsterdam, 2005.
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Surprising Results
Mortazavi SMJ,
Ph.D
• Our study showed that the highest lung cancer
mortality rate was in Galesh Mahaleeh, where the
radon levels were normal.
• On the other hand, the lowest lung cancer
mortality rate was in Ramak, where the highest
concentrations of radon in the dwellings were
found
Mortazavi SMJ, M. Ghiassi-Nejad and M. Rezaiean. Cancer risk due to exposure to high
levels of natural radon in the inhabitants of Ramsar, Iran in: High Levels of Natural
Radiation and Radon Areas: Radiation Dose and Health Effects, T. Sugahara, M.
Morishima, M. Sohrabi, Y Sasaki, I. Hayata, and S. Akiba Eds, pp. 436-437, Elsevier,
Amsterdam, 2005.
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Crude Lung
Cancer Rate
Mortazavi SMJ,
Ph.D
Mortazavi SMJ, M. Ghiassi-Nejad and M. Rezaiean. Cancer risk due to exposure to high
levels of natural radon in the inhabitants of Ramsar, Iran in: High Levels of Natural
Radiation and Radon Areas: Radiation Dose and Health Effects, T. Sugahara, M.
Morishima, M. Sohrabi, Y Sasaki, I. Hayata, and S. Akiba Eds, pp. 436-437, Elsevier,
Amsterdam, 2005.
Adjusted
Lung Cancer
Rate
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Mortazavi SMJ,
Ph.D
Mortazavi SMJ, M. Ghiassi-Nejad and M. Rezaiean. Cancer risk due to exposure to high
levels of natural radon in the inhabitants of Ramsar, Iran in: High Levels of Natural
Radiation and Radon Areas: Radiation Dose and Health Effects, T. Sugahara, M.
Morishima, M. Sohrabi, Y Sasaki, I. Hayata, and S. Akiba Eds, pp. 436-437, Elsevier,
Amsterdam, 2005.
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The Study of Tumor Markers
in High Background Radiation Areas
Source:
S Taeb, SMJ Mortazavi, A Ghaderi, H Mozdarani, MR Kardan, SAR Mortazavi, A
Soleimani, I Nikokar, M Haghani, A Soofi. Alterations of PSA, CA15.3, CA125, Cyfra211, CEA, CA19.9, AFP and Tag72 tumor markers in human blood serum due to long term
exposure to high levels of natural background radiation in Ramsar, Iran. International
Journal of Radiation Research. in press.
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Why Tumor Markers?
• Recently, as no excess
cancer rate was reported
in these areas by
epidemiological studies,
we studied the tumor
markers in the
inhabitants of these
areas to shed some light
on the impact of high
levels of background
radiation on cancer
induction.
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Methods
Mortazavi SMJ, Ph.D
• The level of background gamma radiation as well
as indoor radon was determined using RDS-110
and CR dosimeters.
• Thirty five individuals from a high background
radiation area (HBRA) and 35 individuals from a
normal background radiation area (NBRA) were
randomly selected to participate in the study.
• Commercial ELISA kits (sandwich type ELISA
tests) were used to measure the serum levels of
PSA, CA15.3, CA125, Cyfra21-1, CEA, CA19.9,
AFP and Tag72 tumor markers.
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Results
Mortazavi SMJ, Ph.D
• Among the eight biomarkers investigated, the
means of PSA, CA15.3, CA125, CA19.9 and AFP
concentrations between the HBRAs and NBRAs
were not different.
• However, Cyfra21, CEA and Tag72 in HBRA group
revealed significant increases compared to those of
NBRA group (P<0.05).
• Statistically significant correlation between the
external gamma dose as well as indoor radon level
and the concentration of CEA (P<0.001), Cyfra21(P<0.001) and TAG 72 (P<0.001 and 0.01
respectively) biomarkers were also observed.
Adaptive
Response?
Is it different from Radiation
Hormesis?
What is
Mortazavi SMJ, Ph.D
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Adaptive Response
When large radiation
exposure is preceded by
a small “tickle” dose, the
effect of the large dose is
sometimes diminished
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Ph.D
Adaptive Response Mechanisms
Small doses of radiation appear to:
 Stimulate protective responses
 Triggering DNA repair mechanisms
 Elimination of severely damaged
cells
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Ph.D
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Adaptive response is specific
There seems to be a genetic basis for
adaptive response, since it is
demonstrated only in specific cell
lines, tissues, animal lines and individuals.
It is demonstrated only for specific
biological changes.
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Genetic Basis?
Mortazavi SMJ, Ph.D
Mortazavi SMJ, Ikushima T, and Mozdarani H. Variability of chromosomal radioadaptive
response in human lymphocytes. Iran. J. Radat. Res., 1(1): 55 - 61, 2003.
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Genetic Basis?
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Natural Radiation &
Adaptive Response
High levels of natural
radiation can induce
adaptive responses
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Two survey meters show dose rates of 142 and 143
µSv/h on contact with a bedroom wall
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The 1st report on the
induction of adaptive
response in the
residents of High
Background Radiation
Areas (HBRAs)
105 citations recorded by Web of
Science
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Mortazavi SMJ, Ph.D
Radiofrequency-Induced
Adaptive Response
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Radiofrequency-Induced Adaptive
Response
• In 2009, it was found for the 1st time that preexposure of cultured cells to radiofrequency
radiation induced an adaptive response which
increased the resistance of these cells to
mytomycin C (Sannino et al. , 2009a).
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Radiofrequency-Induced Adaptive Response
Mortazavi SMJ, Ph.D
 Mortazavi et al. also found that laboratory animals
pre-irradiated with radiofrequency radiation were
less susceptible to subsequent lethal effects of high
doses of ionizing radiation (Mortazavi et al. , 2011a,
Mortazavi et al. , 2012a).
 These findings later confirmed by our subsequent
reports (Mortazavi et al. , 2011b, Mortazavi et al,
2012a) as well as the very limited published reports
that investigated the induction of adaptive response
after pre-treatment with microwave radiation (Cao
et al. , 2011, Jiang et al. , 2012, Sannino et al. ,
2009b, Sannino et al. , 2011, Zeni et al. , 2012).
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Radiofrequency-Induced Adaptive Response
 As indicated before, Sannino et al. had previously
reported that pre-exposure of peripheral blood
lymphocytes collected from human volunteers to nonionizing RF radiation (900 MHz, at a peak specific
absorption rate of 10 W/kg for 20 h) increases their
resistance to a challenge dose of mitomycin C (100
ng/ml at 48 h) (Sannino, Sarti, 2009b).
 Later, they confirmed their previous results and
showed that the timing of adapting dose exposure of
radiofrequency plays an important role in the process
of adaptive response induction (Sannino, Zeni, 2011).
2012).
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Mortazavi SMJ, Ph.D
Radiofrequency-Induced Adaptive Response
 On the other hand, Chinese researchers have
recently shown that pre-exposure of mice to nonionizing 900 MHz RF induced adaptive response and
thus reduced the hematopoietic tissue damage from
a subsequent challenge dose of ionizing radiation
(Cao, Xu, 2011).
 Zeni et al. also showed that when lymphocytes were
pre-exposed to RF at 0.3W/kg SAR and then treated
with mitomycin C, these cells showed a significant
reduction in the frequency of micronuclei, compared
with the cells treated with MMC alone (Zeni,
Sannino, 2012).
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Radiofrequency-Induced Adaptive Response
 Jiang et al. also recently used a relatively similar
method as we did previously (using the gamma
radiation as the challenge dose) and indicated that
mice pre-exposed to RF for 3, 5, 7 and 14 days showed
progressively decreased damage and were
significantly different from those exposed to gammaradiation alone (Jiang, Nie, 2012).
 It has also been reported that pre-exposure of Human
promyelocytic leukemia HL-60 cells to 900 MHz
radiofrequency radiation for 1 hour/day for 3 days
had a protective effect in hematopoietic tissue damage
induced by doxorubicin, a chemotherapeutic drug
(Jin et al. , 2012).
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Mortazavi SMJ, Ph.D
Radiofrequency-Induced Adaptive Response
• More recently, Jiang et al. used the micronuclei
(MN) assay as the endpoint and showed that
exposure of mice to both adapting (900MHz RF
radiation) and challenge (3Gy gammaradiation) doses (AD+CD) resulted in a
significant decrease in MN indices compared to
those exposed to CD alone (Jiang et al. , 2013).
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Radiofrequency-Induced Adaptive Response
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Window Theory
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RE Mitchel:
“the adaptive response in
mammalian cells and mammals
operates within a certain window
that can be defined by upper and
lower dose thresholds, typically
between about 1 and 100 mGy
for a single low dose rate
exposure”
(Mitchel 2010)
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Doxorubicin
• Doxorubicin (DOX or adriamycin) is the most
commonly used anticancer drug because of its
efficacy against various tumors.
• Like many other chemotherapeutic drugs,
administration of DOX has toxic effects on
hematopoietic cells
Jin et al. 2012
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Minimum power density
• A preliminary experiment was conducted to
determine the minimum power density needed
for 900 MHz RF pre-exposure to minimize the
damage induced by subsequent exposure to
DOX.
• Cells were pre-exposed to 900 MHz RF at 12,
120 and 1200 mW/cm2 power density for 1
hour/day for 3 days.
Jin et al. 2012
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Jin et al. 2012
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Window Theory in Non-Ionizing Radiation-Induced
Adaptive Responses
Mortazavi SMJ, Ph.D
Dear Editor,
I read with great interest an article by Jin et al. “The Effect of
Combined Exposure of 900 MHz Radiofrequency Fields and
Doxorubicin in HL-60 Cells", published in the Sep 2012 issue of
PLOS ONE Journal (Jin et al. 2012). The authors of the article
reported some interesting findings on the induction of adaptive
response by pre-exposure of HL-60 Cells to radiofrequency (RF)
radiations. As summarized in Table 1, the viability of the cells
exposed to DOX alone was 70.2 ± 0.2 while when cells were exposed
to 900 MHz RF radiation at 12 μW/cm2 before treatment with DOX,
the viability was 82.8 ± 2.1 (P<0.01). RF exposure at higher power
densities significantly decreased the viability (60.7 ± 0.5 and 58.6 ±
0.5 for 120 μW/cm2 and 1200 μW/cm2, respectively). On the other
hand they reported that they had previously conducted a preliminary
experiment to determine the minimum power density for RF preexposures to minimize the damage induced by subsequent exposure
to DOX.
Mortazavi SMJ, Ph.D
Non-responsiveness Phenomenon
Lack of AR in Some Individuals
Reported by:
•Ikushima, T., and Mortazavi SMJ. Radioadaptive response: its
variability in cultured human lymphocytes, In: Biological effects
of low dose radiation, Yamada T, Mothersil C, Mich BD and
Potten CS (eds), pp 81-86, 2000.
•Mortazavi SMJ, Ikushima T, and Mozdarani H. Variability of
chromosomal radioadaptive response in human lymphocytes. Iran.
J. Radat. Res., 1(1): 55 - 61, 2003.
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Immunological Implications
of
RF-Induced Adaptive
Response
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Immune System & Space Research
 Immune system is highly susceptible to different stressors
exist during space flight (Gridley et al. , 2009).
 Dysregulation of the immune system during and
immediately following space missions (Crucian et al. ,
2011, Crucian et al. , 2008).
 Despite the well-known reversible immunological
alterations in short-term spaceflights, the bioeffects of
long-duration spaceflight on neuroimmune responses
have not been completely known so far (Stowe et al. ,
2011).
 Solar and galactic radiation are associated with increased
risk of infection during long term stay of human outside
the Earth’s magnetic field (Zhou et al. , 2012).
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Implications of
RF-Induced Adaptive Response
• Mortazavi et al. have also recently shown that
pre-exposure of BALB/c mice to radiofrequency
radiation emitted from a GSM mobile phone
increases their resistance to a subsequent
bacterial infection (E. coli infection) (Mortazavi
et al. , 2012b).
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Implications of
RF-Induced Adaptive Response
Mortazavi SMJ, Ph.D
 Although there is a report by Plews et al. that indicates
the induction of adaptive response induced by low-dose
whole-body radiation treatments prolonged the
survival of prion-infected mice by reducing oxidative
stress (Plews et al. , 2010), to the best of our knowledge
our study was the first study which showed the
induction of adaptive response as prolonged survival of
Escherichia coli-infected BALB/c mice by pre-exposure
to radiofrequency radiation (non-ionizing radiation).
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Source:
Mortazavi SMJ, Motamedifar M, Mehdizadeh AR, Namdari G, Taheri M. The Effect of Pre-exposure to
Radiofrequency Radiations Emitted from a GSM Mobile Phone on the Suseptibility of BALB/c Mice to
Escherichia coli. Journal of Biomedical Physics and Engineering. 2012; 2(4):139-46.
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Adaptive Response in Space Research
• Concluding Remark:
• Exposure of astronauts to continuous isotropic
galactic cosmic radiation or low levels of
radiofrequency radiation can increase their
resistance against solar particle events or
infections caused by life-threatening
microorganisms.
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Implications of RF-Induced
Adaptive Response in
Space Research
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Adaptive Response in Space
Research
Mortazavi SMJ, Ph.D
 In a report entitled “Adaptive response studies may
help choose astronauts for long-term space travel”,
which published in "Advances in Space Research"
(Mortazavi et al. , 2003), it was previously
hypothesized that screening of the candidates of deep
space missions by Ground-based in vitro adaptive
response tests before any mission can be used to
identify the individuals who respond well to low levels
of ionizing radiation and reveal high magnitudes of
radioadaptive response (Mortazavi et al. , 2005).
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2003
25 citations
according to Scopus
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2003
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Two years after Mortazavi et al 2003
report, NASA agrees that adaptive
response is a puzzling issue in space
radiobiology
• 2005-Cancer specialist Dr. John
Dicello
• “Cells often react in unexpected ways to radiation, notes Dicello.
For example, there's a puzzling phenomenon known as adaptive
response. Sometimes, when tissue is exposed to damaging
radiation, it not only repairs itself, but also learns to repair itself
better next time. How that works is still being investigated”
• “The damage could be less than the two kinds added together -- or
it could be more! There could, perhaps, be an adaptive response in
which lightweight solar protons stimulate repair processes to help
reduce the effects of the heavy cosmic ray ions. Or something
totally unexpected could happen”.
• Mysterious Cancer
http://science.nasa.gov/
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Four
years after
Mortazavi
et al 2003
report, in
2007:
George et al. 2007:
“This study of adaptive response is very interesting and it is important
that the phenomenon be investigated further.
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• Durante and Manti 2008:
• “Another possibility is that an adaptive response to the space environment takes
place after the first exposure, which may confer the exposed individual an increased
radioresistance. Such a response would be similar to that hypothesized to explain
the apparent lack of adverse health effects in VHBRA and HBRA residents. As
pointed out by Mortazavi et al. (2003), radiobiological studies on these areas may
lead to the identification of the cellular and molecular mechanisms by which
susceptibility to genetic damage and cancer is decreased by chronic radiation
exposure, hence helping the astronaut selection process.”
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Mortazavi et al., Advances in Space Research, Vol 31, No. 6, 1543-1552, 2003
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RF-Induced
Adaptive
Response in
Space
Research
• Different
methods that
can be used for
reducing the
risk of
radiation
during deep
space missions
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Mortazavi SMJ, Ph.D
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Responses. , . . Dose Response in press, 2013.
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increased radioresistance to lethal doses of gamma rays after exposure to microwave
radiation and oral intake of flaxseed oil. Iranian Journal of Radiation Research 9, 9-14,
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Emitted by a GSM Mobile Phone Simulator. Dose Response in press, 2012a.
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• Mortazavi, S.M.J., Motamedifar, M., Namdari, G., Taheri, M. Pre-exposure to Radiofrequency
Radiations Emitted from a GSM Mobile Phone Increases Resistance to a Bacterial Infection in
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